NITRIC-OXIDE MEDIATES ANGIOGENESIS INDUCED IN-VIVO BY PLATELET-ACTIVATING-FACTOR AND TUMOR-NECROSIS-FACTOR-ALPHA

We evaluated the role of an endogenous production of nitric oxide (NO) in the in vitro migration of endothelial cells acid in the in vivo an giogenic response elicited by platelet-activating factor (PAF), tamer necrosis factor-alpha (TNF), and basic fibroblast growth factor (bFGF) , The NO synthase inhibitor, N-omega-nitro-L-arginine-methyl ester (L- NAME), but not its enantiomer D-NAME, prevented chemotaxis of endothel ial cells induced in vitro by PAF and by TNF, The motogenic activity o f TNF was also inhibited by WEB 2170, a specific PAF-receptor antagoni st, in contrast, chemotaxis induced by bFGF was not prevented by L-NAM E or by WEB 2170. Angiogenesis was studied in vivo in a murine model i n which Matrigel was used as a vehicle for the delivery of mediators, in this model, the angiogenesis induced by PAF and TNF was inhibited b y WEB 2170 and L-NAME but not by D-NAME, In contrast, angiogenesis ind uced by bFGF was not affected by L-NAME or by WEB 2170. TNF, but not b FGF, induced PAF synthesis within Matrigel. These results suggest that NO mediates the angiogenesis induced by PAF as well as that induced b y TNF, which is dependent on the production of PAF, in contrast, the a ngiogenic effect of bFGF appears to be both PAF and NO independent.